Bacterial protein synthesis starts with N-formyl-methionyl-tRNA (f-Met-tRNAi) and, as a consequence, all newly synthesized polypeptides contain an N-formyl-methionine terminus (f-Met-pp) (Scheme I). Peptide deformylase (PDF) is a metalloenzyme that removes the N-formyl group of the polypeptides as they emerge from the ribosome during the elongation process [Adams, J. M. (1968) J. Mol. Biol. 33, 571-589; Livingston, D. M. and Leder, P. (1969) Biochemistry 8, 435-443; Ball, L. A. and Kaesberg, P. (1973) J. Mol. Biol. 79, 531-537]. Depending on the nature of their second amino acid, polypeptides are further processed by methionine amino peptidase (MAP) to yield the mature protein. Deformylation plays an indispensable role in protein maturation as MAP, an essential enzyme for bacterial growth, cannot hydrolyze N-blocked peptides.

PDF is ubiquitous in bacteria, with at least one pdf gene present in all bacterial genomes sequenced to date.
PDF does not play a role in eukaryotic cytoplasmic protein synthesis which does not involve N-formylation, but nuclear-encoded PDF proteins, containing a chloroplast/mitochondria localization signal, have been identified in parasites, plants and mammals, including humans. PDF is essential in plant and parasite organelles since their genomes encode for a number of proteins which require deformylation for activity, but there is evidence to suggest that this is not the case in animals. In fact, characterization of human mitochondrial PDF has shown that it is much less active than its bacterial counterpart. Furthermore, PDF inhibitors which are active against the human PDF enzyme in vitro have no effect on the growth of normal human cell lines [Nguyen, K. T., Hu, X., Colton, C., Chakrabarti, R., Zhu, M. X. and Pei, D. (2003) Biochemistry 42, 9952-9958].
Thus, PDF inhibitors represent a promising new class of antibacterial agents with a novel mode of action covering a broad-spectrum of pathogens.
PDF inhibitors have been described in the art. Patent applications have been filed on hydrazine-3-oxopropyl hydroxyformamide derivatives of the following formula, see WO 03/101442 and WO2006/055663.

Thus, attempts have been made to prepare compounds that inhibit PDF activity and a number of such compounds have been disclosed in the art. However, there remains a continuing need for inhibitors of PDF which can be used in the treatment of bacterial infections.